A Phase II Clinical Trial Evaluating The Combination Of Lenvatinib Plus Pembrolizumab In Patients With Treatment Naive Metastatic Uveal Melanoma
Phase: PHASE2
Conditions: Melanoma, Uveal
Sponsor: Providence Health & Services

Protocol 2021000802 
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Version Date: 30Jul2024 
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TITLE: A phase II clinical trial evaluating the combination of lenvatinib plus pembrolizumab in 
patients with immune checkpoint inhibitor naïve metastatic uveal melanoma. 
 
IND EXEMPT 
 
 
Principal Investigator: 
Matthew Taylor, MD 
Co-director, Providence Melanoma Program 
Providence Cancer Institute 
4805 NE Glisan St., Portland, Oregon 97123 
Phone: 503-215-6614 
Fax: 503-215-6841 
Email: Matthew.Taylor@providence.org 
 
 
Site(s): 
Providence Cancer Institute, Providence Portland Medical Center 

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TABLE OF CONTENTS 
 
1.0 
TRIAL SUMMARY ..................................................................................................................... 7 
2.0 
TRIAL DESIGN ........................................................................................................................... 7 
2.1 
Trial Design ........................................................................................................................... 7 
2.2 
Trial Schema ......................................................................................................................... 8 
2.3 
Schedule of Activities ............................................................................................................ 9 
3.0 
OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) ................................................. 18 
3.1 
Primary Objective(s), Hypothesis(es), and Endpoint(s) .................................................. 18 
3.2 
Secondary Objective(s), Hypothesis(es), and Endpoint(s) ............................................... 18 
3.3 
Exploratory Objective(s) .................................................................................................... 19 
4.0 
BACKGROUND & RATIONALE ........................................................................................... 19 
4.1 
Background ......................................................................................................................... 19 
4.1.1 Pharmaceutical and Therapeutic Background .............................................................. 20 
4.1.2 Lenvatinib .................................................................................................................... 21 
4.1.3 Lenvatinib + Pembrolizumab ....................................................................................... 21 
4.1.4 Preclinical and Clinical Trial Data ............................................................................... 21 
4.2 
Rationale .............................................................................................................................. 22 
4.2.1 Rationale for the Trial and Selected Population ........................................................... 22 
4.2.2 Justification for Dose ................................................................................................... 22 
4.2.2.1 Planned Exploratory Biomarker Research ........................................................ 23 
5.0 
METHODOLOGY ..................................................................................................................... 23 
5.1 
Study Population ................................................................................................................. 23 
5.1.1 Participant Inclusion Criteria ....................................................................................... 23 

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5.1.2 Participant Exclusion Criteria ...................................................................................... 25 
5.1.3 Lifestyle Considerations .............................................................................................. 27 
5.1.3.1 Meals and Dietary Restrictions .......................................................................... 27 
5.1.3.2 Contraception .................................................................................................... 27 
5.1.3.3 Pregnancy .......................................................................................................... 27 
5.2 
Trial Intervention(s) ........................................................................................................... 28 
5.2.1 Timing of Dose Administration ................................................................................... 28 
5.2.2 Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab and combination therapy ................................................................... 29 
5.2.3 Monitoring Recommendations on lenvatinib ............................................................... 37 
5.2.4 Labeling, Packaging, Storage and Return Of Clinical Supplies ................................... 38 
5.2.4.1 Investigational Product ...................................................................................... 38 
5.2.4.2 Packaging and Labeling Information ................................................................. 38 
5.2.4.3 Clinical Supplies Disclosure .............................................................................. 38 
5.2.4.4 Storage and Handling Requirements ................................................................. 38 
5.2.4.5 Returns and Reconciliation ................................................................................ 39 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) .................................... 39 
5.3.1 Acceptable Concomitant Medications ......................................................................... 39 
5.3.2 Prohibited Concomitant Medications ........................................................................... 39 
5.3.3 Rescue Medications & Supportive Care ...................................................................... 40 
5.4 
Participant Discontinuation Criteria ................................................................................. 41 
5.5 
Participant withdrawal From Study ................................................................................. 42 
5.6 
Clinical Criteria for Early Trial Termination .................................................................. 42 
6.0 
TRIAL ASSESSMENTS AND PROCEDURES ...................................................................... 42 

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6.1 
Trial Procedures .................................................................................................................. 42 
6.1.1 Administrative and General Procedures ....................................................................... 43 
6.1.1.1 Informed Consent .............................................................................................. 43 
6.1.1.2 General Informed Consent ................................................................................ 43 
6.1.1.3 Inclusion/Exclusion Criteria .............................................................................. 44 
6.1.1.4 Medical History ................................................................................................. 44 
6.1.1.5 Prior and Concomitant Medications Review ..................................................... 44 
6.1.1.6 Disease Details and Treatments ......................................................................... 44 
6.1.1.6.1 Disease Details ................................................................................... 44 
6.1.1.6.2 Prior Treatment Details ...................................................................... 44 
6.1.1.6.3 Subsequent Anti-Cancer Therapy Status ............................................ 45 
6.1.1.7 Assignment of Screening Number ..................................................................... 45 
6.1.2 Clinical Procedures/Assessments ................................................................................. 45 
6.1.2.1 Adverse Event (AE) Monitoring ....................................................................... 45 
6.1.2.2 Physical Exam ................................................................................................... 45 
6.1.2.3 Full Physical Exam ............................................................................................ 45 
6.1.2.4 Directed Physical Exam ..................................................................................... 46 
6.1.2.5 Vital Signs ......................................................................................................... 46 
6.1.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Scale ................. 46 
6.1.2.7 Electrocardiograms and ECHO or MUGA ........................................................ 46 
6.1.3 Clinical Safety Laboratory Assessments ...................................................................... 46 
6.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) ......... 47 
6.1.3.2 Pregnancy Testing ............................................................................................. 47 
6.1.4 Tumor Imaging and Assessment of Disease ................................................................ 47 

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6.1.4.1 Initial Tumor Imaging ....................................................................................... 48 
6.1.4.2 Tumor Imaging During the Study ...................................................................... 48 
6.1.4.3 End of Treatment and Follow-up Tumor Imaging ............................................ 49 
6.1.4.4 RECIST 1.1 Assessment of Disease .................................................................. 49 
6.1.4.5 iRECIST Assessment of Disease ....................................................................... 49 
6.1.5 Tumor Tissue Collection and Correlative Studies Blood Sampling ............................ 52 
6.1.6 Other Procedures .......................................................................................................... 52 
6.1.6.1 Discontinuation and withdrawal ........................................................................ 52 
6.1.7 Visit Requirements ....................................................................................................... 53 
6.1.7.1 Screening ........................................................................................................... 53 
6.1.7.1.1 Screening Period ................................................................................. 53 
6.1.7.2 Treatment Period ............................................................................................... 53 
6.1.7.3 Post-Treatment Visits ........................................................................................ 53 
6.1.7.3.1 Safety Follow-Up Visit ....................................................................... 53 
6.1.7.3.2 Efficacy Follow-up Visits ................................................................... 53 
6.1.7.3.3 Survival Follow-up Contacts .............................................................. 53 
6.1.7.3.4 Post Study ........................................................................................... 54 
6.2 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety 
Events ................................................................................................................................... 54 
6.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety 
Event Information ........................................................................................................ 54 
6.2.2 Method of Detecting AEs, SAEs, and Other Reportable Safety Events ...................... 56 
6.2.3 Follow-up of AE, SAE, and Other Reportable Safety Event Information ................... 56 
6.2.4 Sponsor Responsibility for Reporting Adverse Events ................................................ 56 
6.2.5 Pregnancy and Exposure During Breastfeeding ........................................................... 56 

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6.2.6 Events of Clinical Interest (ECIs) ................................................................................ 57 
7.0 
STATISTICAL ANALYSIS PLAN .......................................................................................... 57 
7.1 
Statistical Analysis Plan Summary .................................................................................... 57 
7.2 
Statistical Analysis Plan ...................................................................................................... 58 
8.0 
ADMINISTRATIVE AND REGULATORY DETAILS ........................................................ 58 
8.1 
Data Reporting .................................................................................................................... 58 
8.2 
Continuing Review and Final Reports .............................................................................. 59 
8.3 
Protocol Modifications and Amendments ......................................................................... 59 
8.4 
Record Retention ................................................................................................................. 59 
8.5 
Study Monitoring ................................................................................................................ 59 
8.6 
Quality Assurance Plan ...................................................................................................... 60 
8.7 
Safety Monitoring Plan ....................................................................................................... 61 
9.0 
REFERENCES ........................................................................................................................... 61 
10.0 
APPENDICES ............................................................................................................................ 66 
Appendix 1: ECOG Performance Status ...................................................................................... 66 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 67 
Appendix 3: Contraceptive Guidance and Pregnancy Testing ................................................... 69 
Appendix 4: Description of the iRECIST Process for Assessment of Disease Progression ..... 72 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................... 76 
 

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1.0 TRIAL SUMMARY 
 
Abbreviated Title 
Lenvatinib plus pembrolizumab in patients with immune checkpoint 
inhibitor naïve metastatic uveal melanoma 
Trial Phase 
Phase II 
Clinical Indication 
Treatment of participants with immune checkpoint inhibitor naïve 
metastatic uveal melanoma 
Trial Type 
Interventional 
Type of control 
n/a 
Route of administration 
Oral and IV 
Treatment Groups 
Single arm: Lenvatinib 20 mg daily plus pembrolizumab 200 mg IV every 
3 weeks. 
Number of trial participants 
30 
Estimated enrollment period 
20 months 
Estimated duration of trial 
48 months (FPFV to LPLV) 
Duration of Participation 
Subjects will participate in the clinical trial from the time of signing the 
ICF until the final protocol specified contact. Subjects who discontinue 
treatment for reasons other than disease progression or treatment related 
toxicity will have post-treatment follow-up until documented radiographic 
evidence of disease progression (per iRECIST), initiation of a subsequent 
anti-cancer therapy, death, pregnancy, withdrawal of consent, lost to 
follow up or the end of the clinical trial. 
Estimated average length of 
treatment per patient 
6 months 
 
2.0 TRIAL DESIGN 
 
2.1 Trial Design 
 
This is a phase II, single arm, single institution clinical trial. Adults (age≥18 years-old) with 
immune checkpoint inhibitor naïve metastatic uveal melanoma will be evaluated for eligibility. 
Eligible participants will be treated with the combination of Lenvatinib 20 mg daily + 
pembrolizumab 200 mg IV every 3 weeks for a maximum of 2 years. 

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2.2 Trial Schema 
 

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2.3 Schedule of Activities 
 
Table 1 Study Schedule of Activities 
 
Study Period: 
Screening 
Intervention (21-Day Cycles) 
End of 
Treatment 
Post treatment Visits 
Notes 
Visit Number/Title: 
1/Screening 
C1 
C2 
C3 
C4 
C5 
C6 
to 
C35 
≥ 
C36 
Safety 
Follow- 
up 
Efficacy 
Follow- 
up 
Survival 
FU 
Cycle Day 
1 
8 
15 
1 
15 
1 
1 
1 
1 
1 
Scheduling Window 
(days) 
-42 
to 
– 
1 
-28 
to 
- 
1 
±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At time 
of 
treatment 
discontin
uation 
Approx. 
30d after 
last 
dose 
(± 7d) 
Q6W 
(Y1) or 
Q9W 
(Y2+) 
(± 7d) 
Q12Wa 
(± 14d) 
Administrative Procedures 
Informed Consent 
X 
Inclusion/Exclusion 
Criteria 
X 
Demographics and 
Medical History 
X 
Includes smoking and 
tobacco use. 
Prior Treatment 
X 
Prior/Concomitant 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subsequent 
Antineoplastic Therapy 
Status 
X 
X 
X 
X 
Survival Status 
 
 
X 
Participants may be 
contacted for survival status 
at any time during the 
course of the study. 

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Study Period: 
Screening 
Intervention (21-Day Cycles) 
 
End of 
Treatment 
Post treatment Visits 
Notes 
Visit Number/Title: 
1/Screening 
C1 
C2 
C3 
C4 
C5 
C6 
to 
C35 
≥ 
C36 
Safety 
Follow- 
up 
Efficacy 
Follow-up 
Survival 
FU 
Cycle Day 
1 
8 
15 
1 
15 
1 
1 
1 
1 
1 
Scheduling Window 
(days) 
-42 
to 
– 
1 
-28 
to - 
1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At time 
of 
treatment 
discontin
uation 
Approx. 
30d after 
last 
dose 
(± 7d) 
Q6W 
(Y1) or 
Q9W 
(Y2+) 
(± 7d) 
Q12Wa 
(± 14d) 
Study Intervention Administration 
Lenvatinib Dispensing 
X 
X 
X 
X 
X 
X 
X 
Lenvatinib 
Administration 
PO QD 
Taken at home  
Lenvatinib 
container returned 
X 
X 
X 
X 
X 
X 
Lenvatinib will be held for 7 
days prior to biopsy and will 
resume 2 days post biopsy. 
Pembrolizumab 
Administration 
IV Q3W 
X 
X 
X 
X 
X 
X 
Efficacy Procedure 
Tumor Biopsy 
Collection 
X 
 
 
XC 
Fresh tumor biopsy 
specimens will be collected at 
Screening and at C3D8 from 
at least 15 subjects (in no 
certain order). Archival tissue 
may be used in place of pre-
treatment biopsy.  
Tumor Imaging 
(chest, abdomen, & 
pelvis) and iRECIST 
Assessment 
Note: Imaging of the 
brain required only at 
screening. 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Imaging is performed at 
Screening, Week 9 and every 
9 weeks (± 7 days) during 
Year 1. After Year 1, imaging 
is performed every 12 weeks 
(±7 days). This schedule will 
be maintained regardless of 
treatment delays. 

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Study Period: 
Screening 
Intervention (21-Day Cycles) 
End of 
Treatment 
Post treatment Visits 
Notes 
Visit Number/Title: 
1/Screening 
C1 
C2 
C3 
C4 
C5 
C6 
to 
C35 
≥ 
C36 
Safety 
Follow- 
up 
Efficacy 
Follow- 
up 
Survival 
FU 
Cycle Day 
1 
8 
15 
1 
15 
1 
1 
1 
1 
1 
Scheduling Window 
(days) 
-42 
to - 
1 
-28 
to - 
1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At time 
of 
treatment 
discontin
uation 
Approx. 
30d after 
last 
dose 
(± 7d) 
Q6W 
(Y1) or 
Q9W 
(Y2+) 
(± 7d) 
Q12Wa 
(± 14d) 
Safety Procedures 
AE/SAE Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Report AEs occurring 
within 30 days after the last 
dose of study intervention. 
Report SAEs occurring 
within 90 days after the last 
dose of study intervention, 
or 30 days after the last dose 
of study intervention if a 
new anticancer therapy is 
initiated, whichever is first. 
Full Physical 
Examination 
X 
X 
Height 
X 
Directed Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contact 
 
X 
 
 
 
 
 
 
 
 
 
The investigator or medically 
qualified designee (consistent 
with local requirements) will 
assess participants for 
development of early toxicity. 
An unscheduled visit can 
occur before C1D15 if 
necessary for safety. 
 
 

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Study Period: 
Screening 
Intervention (21-Day Cycles) 
End of 
Treatment 
Post treatment Visits 
Notes 
Visit Number/Title: 
1/Screening 
C1 
C2 
C3 
C4 
C5 
C6 
to 
C35 
≥ 
C36 
Safety 
Follow- 
up 
Efficacy 
Follow- 
up 
Survival 
FU 
Cycle Day 
1 
8 
15 
1 
15 
1 
1 
1 
1 
1 
Scheduling Window 
(days) 
-42 
to - 
1 
-28 
to - 
1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At time 
of 
treatment 
discontin
uation 
Approx. 
30d after 
last 
dose 
(± 7d) 
Q6W 
(Y1) or 
Q9W 
(Y2+) 
(± 7d) 
Q12Wa 
(± 14d) 
Vital Signs 
(resting BP, heart rate, 
RR, and temp) and 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
The Day 15 visit is 
mandatory for C1 and C2. 
During C3 and subsequent 
cycles, participants may return 
for the D15 visit if BP 
monitoring is required. 
12-lead ECG with 
QTcF Determination 
(Single) 
X 
X 
X 
X 
X 
X 
X 
Every 4 cycles. ECG at 
Screening, C1D1, C2D1, D1of 
every fourth cycle (12 weeks) 
thereafter (e.g., C6, C10, C14, 
etc.), EOT, and safety follow-up. 
For high-risk participants 
(Section 6.1.2.7), conduct ECG 
monitoring every cycle. If 
Lenvatinib is discontinued, 
ECGs are only required at the 
EOT and Safety Follow-up visits. 

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Study Period: 
Screening 
Intervention (21-Day Cycles) 
 
End of 
Treatment 
Post treatment Visits 
Notes 
Visit Number/Title: 
1/Screening 
C1 
C2 
C3 
C4 
C5 
C6 
to 
C35 
≥ 
C36 
Safety 
Follow- 
up 
Efficacy 
Follow-up 
Survival 
FU 
Cycle Day 
1 
8 
15 
1 
15 
1 
1 
1 
1 
1 
Scheduling Window 
(days) 
-42 
to - 
1 
-28 
to - 
1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At time 
of 
treatment 
discontin
uation 
Approx. 
30d after 
last 
dose 
(± 7d) 
Q6W 
(Y1) or 
Q9W 
(Y2+) 
(± 7d) 
Q12Wa 
(± 14d) 
MUGA Scan or 
ECHO 
X 
X 
Additional LVEF 
assessments may be 
performed as clinically 
indicated. 
ECOG Performance 
Status 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status obtained 
on C1D1 may also be used as the 
screening value to determine 
eligibility. 
*Screening ECOG within 7 
days before initiation of study 
intervention. If performed within 
7 days prior to day one ECOG 
does not need to be repeated on 
Day 1  
Laboratory Procedures/Assessments (Local Laboratory) 
Serum β-hCG 
Pregnancy Test 
(WOCBP only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WOCBP require a negative test. 
If more than 24 hours have 
elapsed before the first dose of 
study intervention, another 
pregnancy test is required. A 
serum pregnancy test will be 
performed per Appendix 2. 

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Study Period: 
Screening 
Intervention (21-Day Cycles) 
End of 
Treatment 
Post treatment Visits 
Notes 
Visit Number/Title: 
1/Screening 
C1 
C2 
C3 
C4 
C5 C6 to 
C35 
≥ 
C36 
Safety 
Follow-up 
Efficacy 
Follow-up 
Survival 
FU 
Cycle Day 
1 
8 
15 
1 
15 
1 
1 
1 
1 
1 
Scheduling Window 
(days) 
-42 
to - 
1 
-28 
to - 
1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At time 
of 
treatment 
discontin
uation 
Approx. 
30d after 
last dose 
(± 7d) 
Q6W 
(Y1) or 
Q9W 
(Y2+) 
(± 7d) 
Q12Wa 
(± 14d) 
Serum FSH 
(WONCBP only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the absence of 12 months of 
amenorrhea, confirmation with 2 
FSH measurements in 
postmenopausal range is required. 
HIV, Hepatitis B, and 
Hepatitis C 
X* 
*Required at Screening only 
if mandated by local health 
authority 
Hematology 
X* 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Labs obtained on C1D1 may also 
be used as the screening value to 
determine eligibility. 
*Perform screening 
laboratory tests within 7 days 
before the first dose. If 
performed within 7 days prior 
to day one CMP does not 
need to be repeated on Day 1 
Chemistry 
X* 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Thyroid Function Tests 
(LDH, Free T4, TSH) 
X* 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
Labs obtained on C1D1 may 
also be used as the screening 
value to determine eligibility. 
*Perform screening 
laboratory tests within 7 days 
before first dose, then at C2 
and every 2 cycles thereafter 
(C4, C6, etc.) If performed 
within 7 days prior to day one 
thyroid function and LDH 
does not need to be repeated 
on Day 1 

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Study Period: 
Screening 
Intervention (21-Day Cycles) 
End of 
Treatment 
Post treatment Visits 
Notes 
Visit Number/Title: 
1/Screening 
C1 
C2 
C3 
C4 
C5 
C6 
to 
C35 
≥ 
C36 
Safety 
Follow- 
up 
Efficacy 
Follow-up 
Survival 
FU 
Cycle Day 
1 
8 
15 
1 
15 
1 
1 
1 
1 
1 
Scheduling Window 
(days) 
-42 
to - 
1 
-28 
to - 
1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At time 
of 
treatment 
discontin
uation 
Approx. 
30d after 
last 
dose 
(± 7d) 
Q6W 
(Y1) or 
Q9W 
(Y2+) 
(± 7d) 
Q12Wa 
(± 14d) 
Urine Dipstick 
Testing 
 
X* 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
After C1, collect samples at 
C1D15 and C2 D15 and up to 3 
days before D1 of each cycle. If 
lenvatinib is discontinued, urine 
dipstick testing no longer 
required. Urine dipstick testing 
(or urinalysis) obtained and 
reviewed on C1D1 may also be 
used as the screening value to 
determine eligibility. If 24-hour 
urine collection for quantitative 
assessment of proteinuria is 
required, C1D1 is postponed to 
after proteinuria result available. 
*Perform screening urinalysis 
tests within 7 days before the first 
dose.  If performed within 7 days 
prior to day one urine dipstick  
does not need to be repeated on 
Day 1 

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Study Period: 
Screening 
Intervention (21-Day Cycles) 
End of 
Treatment 
Post treatment Visits 
Notes 
Visit Number/Title: 
1/Screening 
C1 
C2 
C3 
C4 
C5 
C6 
to 
C35 
≥ 
C36 
Safety 
Follow-up 
Efficacy 
Follow- 
up 
Survival 
FU 
Cycle Day 
1 
8 
15 
1 
15 
1 
1 
1 
1 
1 
Scheduling Window 
(days) 
-42 
to - 
1 
-28 
to - 
1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At time 
of 
treatment 
discontin
uation 
Approx. 
30d after 
last 
dose 
(± 7d) 
Q6W 
(Y1) or 
Q9W 
(Y2+) 
(± 7d) 
Q12Wa 
(± 14d) 
INR or PT and aPTT 
 
X* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Labs obtained and reviewed on 
C1D1 may also be used as the 
screening value to determine 
eligibility. 
Additional testing is to be 
performed as clinically 
indicated for participants 
taking anticoagulants. 
*Perform screening 
laboratory tests within 
7 days before the first dose. If 
performed within 7 days prior to 
day one INR or PT and aPTT does 
not need to be repeated on Day 1 
Biomarkers 
Blood for Research 
X 
 
Xb 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Collect at screening and pre dose 
on D1 of Cycles 1-6. 
Optional Specimen 
for Banking 
X 
 
Xb 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Optional blood collection for 
specimen banking, collect at 
screening and pre dose on D1 of 
Cycles 1-6. 
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BP = blood pressure; β-HCG; = β human chorionic gonadotropin; C = cycle; CXDY= Cycle X Day Y; 
d = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiogram; EOT = end of treatment; FSH = follicle-stimulating hormone; FU = 
follow-up; HIV = human immunodeficiency virus; INR = international normalized ratio; LVEF = left ventricular ejection fraction; MUGA = multigated acquisition; PT = prothrombin 
time; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QTcF = QT interval corrected with Fridericia’s formula; RNA= ribonucleic acid; RR = respiratory rate; 
SAE = serious adverse event; SoA= schedule of activities; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential; WONCBP = women of 
nonchildbearing potential. 
 
a. If the poststudy visit occurs less than 14 days after the last dose of study intervention, a subsequent follow-up telephone call should be made at 14 days post the last dose of study 
intervention to determine of any AEs have occurred since the poststudy clinic visit. 

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b. Correlative and optional specimen banking samples collected for Screening may be used for C1D1 if the collection is within 3 days prior to C1D1. 
c. Collect at C3D8 
 

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3.0 OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) 
 
3.1 
Primary Objective(s), Hypothesis(es), and Endpoint(s) 
 
(1) Objective: To evaluate the effect of lenvatinib + pembrolizumab on progression free survival. 
 
Hypothesis: Treatment with Lenvatinib + pembrolizumab will result in improved progression 
free survival as compared with previously reported systemic therapies including pembrolizumab 
monotherapy, ipilimumab + nivolumab and tebentafusp. 
 
Primary Endpoint: Progression free survival, defined as the time from enrollment to the first 
documented evidence of disease progression or death. 
 
3.2 
Secondary Objective(s), Hypothesis(es), and Endpoint(s) 
 
(1) Objective: To evaluate the objective response rate resulting from treatment with Lenvatinib + 
pembrolizumab. 
 
Hypothesis: Treatment with Lenvatinib + pembrolizumab will result in an improved objective 
response rate as compared with previously reported therapies including pembrolizumab 
monotherapy, ipilimumab + nivolumab and tebentafusp. 
 
Secondary Endpoint: Objective response rate (complete and partial responses assessed by 
iRECIST) 
 
(2) Objective: To evaluate the effect of treatment with Lenvatinib + pembrolizumab on overall 
survival. 
 
Hypothesis: Treatment with Lenvatinib + pembrolizumab will result in improved overall 
survival as compared with previously reported therapies including pembrolizumab monotherapy, 
ipilimumab + nivolumab and tebentafusp. 
 
Secondary Endpoint: Overall survival, defined as the time from enrollment to death (resulting 
from any cause). 
 
(3) Objective: To evaluate the safety and tolerability of treatment with Lenvatinib + pembrolizumab 
in patients with metastatic uveal melanoma. 
 
Hypothesis: Treatment with Lenvatinib + pembrolizumab will demonstrate an acceptable 
toxicity profile in patients with metastatic uveal melanoma. 
 
Secondary Endpoint: 
 
• Adverse events (per CTCAE v5.0) 

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• Frequency of treatment interruption, dose reduction, and treatment discontinuation due 
to treatment related adverse events (TRAE). 
 
3.3 
Exploratory Objective(s) 
 
(1) Objective: 
 
To evaluate correlative biomarkers from tumor and blood specimens in patients treated with 
Lenvatinib + pembrolizumab. 
 
Hypothesis: Treatment with Lenvatinib + pembrolizumab will result in changes in the tumor 
infiltrating immune cell profile and tumor gene expression profile. 
 
Secondary Endpoint: 
 
• Multiplex immunohistochemical analysis of tumor biopsy specimens for characterization 
of the tumor immune profile. 
 
• Gene expression profiling of tumor biopsy specimens by RNAseq. 
4.0 BACKGROUND & RATIONALE 
4.1 Background 
 
Uveal melanoma 
Metastatic uveal melanoma is associated with a very poor prognosis with median survival of 6-12 
months [1]. Unfortunately, systemic therapy with immune checkpoint inhibitors has demonstrated 
inadequate efficacy. In a phase II clinical trial with ipilimumab, no objective responses were observed 
and the median progression free survival (PFS) was 2.8 months [2]. A small phase II clinical trial (17 
patients) evaluated the efficacy of pembrolizumab monotherapy. Two out of the 17 patients had an 
objective response (11.7%) and median PFS was 3.8 months [3]. Treatment with the combination of 
ipilimumab + nivolumab was evaluated in a phase II clinical trial that showed an objective response 
rate (ORR) of 18% with median PFS of 5.5 months and median overall survival of 19.1 months [4]. 
The results of the phase III clinical trial evaluating the bispecific fusion protein Tebentafusp in patients 
with metastatic uveal melanoma were reported at the 2021 AACR annual meeting. In this clinical trial, 
patients were randomly assigned (2:1) to either treatment with tebentafusp or investigator choice of 
therapy (pembrolizumab, ipilimumab or dacarbazine). The authors reported a median overall survival 
of almost 22 months for tebentafusp compared with 16 months in the investigator choice arm. 
Tebentafusp resulted in an ORR of 9% [5]. As such, effective therapies for patients with metastatic 
uveal melanoma represents a significant unmet clinical need. 
 
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- 

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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). 
 
Lenvatinib (E7080 or MK-7902) is a potent small molecule inhibitor of multiple kinases including 
vascular endothelial growth factor receptors (VEGFR) 1-3, fibroblast growth factor receptors (FGFR) 
1-4, platelet derived growth factor receptor alpha (PDGFRα), KIT and RET. Several of these kinases 
are overexpressed by various cancers and contribute to tumor proliferation, invasion, metastasis and 
immune suppression in the tumor microenvironment [6]. 
 
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 
Tcells/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) 
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- 
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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 metastatic 
immune checkpoint inhibitor naïve uveal melanoma. 
 
4.1.2 Lenvatinib 
 
VEGF signaling within the tumor microenvironment contributes to tumor proliferation, angiogenesis, 
and exerts multiple immune suppressive effects which disrupt anti-tumor immunity. Specifically, high 
levels of VEGF within the tumor microenvironment is associated with increased tumor infiltration of 
regulatory T cells (Treg). Additionally, VEGF signaling in activated T cells results in increased 
expression of multiple inhibitory immune receptors including PD-1, CTLA-4, TIM-3 and LAG-3 [18]. 
 
Lenvatinib has demonstrated potent antiangiogenic and antiproliferative activity in preclinical models. 
In a syngeneic mouse tumor model, treatment with Lenvatinib resulted in increased tumor infiltration 
of activated CD8+ T cells (expressing granzyme B and IFN-γ) and plasmacytoid dendritic cells and 
decreased the number of tumor associated macrophages (TAM) [19]. Lenvatinib has also resulted in 
decreased tumor infiltration of Tregs in patients with advanced renal cell carcinoma [20]. 
 
4.1.3 Lenvatinib + Pembrolizumab 
 
Multiple factors contribute to tumor immune evasion which include impaired T cell priming and 
activation by antigen presenting cells, impaired T cell trafficking into tumors, exhaustion of tumor- 
specific T cells, immunosuppressive cytokines (TGFβ, IL-10, etc.), and others [21]. Due to the 
immunosuppressive roles of VEGF and PD-1 signaling in tumors, pre-clinical testing was done to 
evaluate the effect of Lenvatinib + pembrolizumab in syngeneic mouse tumor models. Using the 
CT26 CRC and Hepa1-6 HCC mouse tumor models, Lenvatinib + pembrolizumab resulted in 
improved anti-tumor activity than either agent alone [22]. Based on the mechanistic rationale and 
encouraging pre-clinical data, the Study 111/Keynote-146 was designed to evaluate the safety, 
tolerability and efficacy of the combination of Lenvatinib + pembrolizumab in patients with 
advanced solid tumors. This clinical trial showed that Lenvatinib 20 mg/day + pembrolizumab 200 
mg IV every 3 weeks exhibited an acceptable safety profile and significant preliminary anti-tumor 
efficacy. Subsequent clinical trials in patients with advanced endometrial carcinoma and renal cell 
carcinoma confirmed excellent anti-tumor activity. These results led to the FDA approval of 
Lenvatinib + Pembrolizumab for patients with metastatic endometrial cancer and metastatic renal 
cell carcinoma [23]. 
 
4.1.4 Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 

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4.2 Rationale 
 
4.2.1 Rationale for the Trial and Selected Population 
 
The combination of Lenvatinib + pembrolizumab has demonstrated excellent clinical efficacy in 
patients with metastatic endometrial cancer as well as metastatic renal cell carcinoma. Of note, it 
appears that the combination of these drugs may result in a synergistic therapeutic effect rather than 
merely an additive benefit. Consequently, this combination is now being evaluated across a broad range 
of advanced solid tumors. 
 
Uveal melanomas express high levels of the immunosuppressive molecules VEGF and FGF [24]. 
Consequently, targeting VEGF and FGF signaling pathways in the tumor microenvironment represents 
an attractive approach to decrease the local immunosuppression. The anticipated effect of blockade of 
both VEGF and PD-1 signaling will be to modulate the tumor microenvironment by increasing tumor 
infiltration of CD8+ T cells, decreasing intratumoral Tregs and TAMs and reinvigorating exhausted 
tumor-specific CD8+ T cells. It is noteworthy that high numbers of Tregs in uveal melanoma metastases 
has been correlated with poor response to immune checkpoint inhibitors [25]. As such, the capacity of 
Lenvatinib to decrease the number of tumor infiltrating Tregs may represent a significant mechanism 
of enhancing anti-tumor immunity when used in combination with pembrolizumab. 
 
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 in melanoma and NSCLC indications demonstrating flat 
dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W, representing 
an approximate 5- to 7.5-fold exposure range (refer to IB, Section 5.2.2) 
• Population PK analysis showing that both fixed dosing and weight-based dosing provides similar 
control of PK variability with considerable overlap in the distributions of exposures, supporting 
suitability of 200 mg Q3W 
• 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 
The dose for Lenvatinib in this clinical trial will be 20 mg daily. This dose of Lenvatinib has been shown 
to be safe and well tolerated by several clinical trials using this combination [26]. The combination of 
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FDA for treatment of patients with metastatic renal cell carcinoma and metastatic endometrial carcinoma 
that is not microsatellite instability-high or mismatch repair deficient (see Lenvatinib package insert). 
 
4.2.2.1 Planned Exploratory Biomarker Research 
 
Paired fresh tumor biopsy specimens will be collected (pre-treatment and cycle 3 day 8 ) from at least 
15 subjects (in no certain order). Subjects with tumor metastases that are not amenable to image guided 
biopsies or who have a contraindication to biopsy (such as anticoagulation therapy that cannot be 
interrupted for a biopsy) are still eligible for participation in the clinical trial without the biopsies. 
Archival tissue may be used in place of pre-treatment biopsy. These specimens will be banked for 
biomarker analysis that will include tumor immune cell profiling and gene expression analysis. 
Biomarker analysis will be performed for evaluation of predictive and/or prognostic biomarkers of tumor 
response and survival. 
 
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 18 years of age on the day of signing informed consent 
with histologically confirmed diagnosis of uveal melanoma that is unresectable or metastatic will 
be enrolled in this study. 
 
2. 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 Lenvatinib and refrain 
from donating sperm during this period. 
 
3. Female participants: 
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 
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 120 days post pembrolizumab or post Lenvatinib whichever 
occurs last. 
 
4. The participant (or legally acceptable representative if applicable) provides written informed 
consent for the trial. 

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5. Have measurable disease based on iRECIST. Lesions situated in a previously irradiated area are 
considered measurable if progression has been demonstrated in such lesions. 
 
6. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a 
tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks 
are preferred to slides. If slides are only available, ten slides would be required. Newly obtained 
biopsies are preferred to archived tissue. 
 
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation 
of ECOG is to be performed within 7 days prior to the first dose of study intervention. 
 
8. Have adequate organ function as defined in the following table (Table 2). Specimens must be 
collected within 7 days prior to the start of study intervention. 
 
9. Paired fresh tumor biopsy specimens (to be collected pre- treatment and cycle 3 day 8 ) will be 
collected for at least 15 patients (in no certain order) who consent. Subjects with tumor 
metastases that are not amenable to image guided biopsies or who have a contraindication to 
biopsy (including but not limited to anticoagulation therapy that cannot be interrupted for a 
biopsy) are still eligible for participation in the clinical trial without undergoing biopsies. 
Archival tissue may be used in place of pre-treatment biopsy. 
 
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 (patients with clinical 
evidence of Gilbert’s syndrome and elevated bilirubin are 
eligible for participation). 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases) 

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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. 
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 serum pregnancy test within 24 hours prior to the first dose of 
study intervention (see Appendix 3). 
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 (e.g., CTLA-4, OX-40, CD137). 
Prior therapy with Tebentafusp is permitted. Prior liver directed therapy is permitted (including 
but not limited to radioembolization, chemoembolization, immunoembolization, radio- 
frequency ablation, external beam radiation and resection). 
 
3. Participants previously treated with radiation therapy must have recovered from all radiation- 
related toxicities and not require corticosteroids. 
 
4. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of 
study drug. Administration of killed-virus vaccines and mRNA vaccines are allowed. 
 
5. 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. 
 
6. 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, early stage bladder cancer, or carcinoma in situ (e.g., breast carcinoma, cervical cancer 
in situ) that have undergone potentially curative therapy are not excluded. 
 
7. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically stable, i.e. 

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without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat 
imaging should be performed during study screening), clinically stable and without requirement 
of steroid treatment for at least 14 days prior to first dose of study intervention. 
 
8. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
9. 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. 
 
10. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or 
has current pneumonitis/interstitial lung disease. 
 
11. Has an active infection requiring systemic therapy. 
 
12. 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. 
 
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
 
14. 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. 
 
15. Has had an allogenic tissue/solid organ transplant. 
 
16. Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an 
optimized regimen of antihypertensive medication. 
 
17. Significant cardiovascular impairment: history of congestive heart failure greater than New York 
Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 
months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at 
Screening. 
 
18. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor 
invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of 
the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following 
lenvatinib therapy. 

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19. Subjects having ≥2+ proteinuria on urine dipstick testing. However, subjects with ≥2+ 
proteinuria on urine dipstick testing may undergo a 24-hour urine collection for quantitative 
assessment of proteinuria. Subjects with <1 g/24-hour proteinuria are eligible for participation. 
 
20. Subjects who have not recovered adequately from any toxicity from other anti- cancer treatment 
regimens and/or complications from major surgery prior to starting therapy. Withhold lenvatinib 
for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following 
major surgery and until adequate wound healing. 
 
21. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) 
test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). 
 
22. Females of child-bearing potential must be willing to use effective contraception during study 
and for 120 days after the last dose 
 
23. The participant has severe hypersensitivity (≥Grade 3) to lenvatinib and/or any of its excipients 
 
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 and lenvatinib 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). 
 
5.1.3.3 Pregnancy 
 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab and 
lenvatinib, 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 Merck 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 Merck. If a male participant impregnates his female partner, the 

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study personnel at the site must be informed immediately and the pregnancy must be reported to Merck 
and followed as described in Section 6.2. 
 
5.2 Trial Intervention(s) 
 
The intervention(s) to be used in this trial is outlined below in Table 3. 
 
Table 3 Trial Intervention(s) 
 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Lenvatinib 
20 mg 
QD 
Oral 
QD, no treatment 
duration limit 
Experimental 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle for 2 years 
maximum 
Experimental 
Abbreviations: IV = intravenous; QD = once daily 
 
Trial intervention(s) should begin on the day of or as close as possible to the date on which intervention 
is allocated/assigned. 
 
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 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). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
Lenvatinib 20 mg will be administered in an oral dose to be taken once daily. Capsules are packaged 
in cold form blisters or high-density polyethylene bottles with a polypropylene cap and desiccant. The 
blisters and bottles should be stored under room temperature. 

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5.2.2 Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab and combination therapy 
 
AEs associated with pembrolizumab exposure, including coadministration with additional compounds, 
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/combination treatment and may 
affect more than one body system simultaneously. Therefore, early recognition and initiation of 
treatment is critical to reduce complications. Based on existing clinical study data, most irAEs were 
reversible and could be managed with interruptions of pembrolizumab/combination treatment, 
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/combination treatment 
are provided in Table 4. 
 
Attribution of Toxicity: 
 
When study interventions are administered in combination, attribution of an adverse event to a single 
component is likely to be difficult. Therefore, while the investigator may attribute a toxicity event to 
lenvatinib or to pembrolizumab alone, both interventions must be held according to the criteria in 
Table 4 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Associated with Pembrolizumab. 
 
Holding Study Interventions: 
 
When study interventions are administered in combination, if the AE is considered immune-related, 
both interventions should be held according to recommended dose modifications. 
 
Restarting Study Interventions: 
 
Participants may not have any dose modifications (no change in dose or schedule) of pembrolizumab 
in this study, as described in Table 4. 
 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant must 
be discontinued from all study interventions. 
• If the toxicities do resolve and conditions are aligned with what is defined in Table 4, the 
combination of lenvatinib and pembrolizumab may be restarted at the discretion of the investigator. 
In these cases where the toxicity is attributed to the combination or to lenvatinib alone, re-initiation 
of pembrolizumab as a monotherapy may be considered at the principal investigator’s discretion. 

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Table 4 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
monotherapy and Immunotherapy (IO) Combinations 
 
 
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 to 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 
· Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
· Monitor participants for signs and symptoms of 
enterocolitis (i.e., diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (i.e., peritoneal signs 
and ileus) 
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. Study intervention 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 study intervention treatment. 
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Recurrent 
Grade 
3 
or 
Grade 4 
Permanently 
discontinue 
· 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 to 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 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM 
or 
Hyperglycemia 
New 
onset 
T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence 
 of 
b-cell failure 
Withhold d 
· Initiate insulin replacement therapy for 
participants with T1DM 
· Administer antihyperglycemic in 
participants with hyperglycemia 
· Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
· Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
· Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Hyperthyroidism 
Grade 2 
Continue 
· Treat with nonselective beta-blockers 
(e.g., 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 
(e.g., levothyroxine or liothyronine) per 
standard of care 
· Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according 
 to 
increased 
creatinine 
or 
acute 
kidney 
injury 
Grade 2 
Withhold 
· Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper 
· Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 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 
Myocarditis 
Grade 1 
Withhold 
· Based on severity of AE administer 
corticosteroids 
· Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
· Based on severity of AE administer 
corticosteroids 
· Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
All Other irAEs 
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 based 
on the event e 
Recurrent 
Grade 3 
or 
Grade 4 
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b  AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 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: encephalitis and other clinically important irAEs (e.g., vasculitis and sclerosing cholangitis). 
 
 
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 

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hours of completion of infusion. Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5. 
Table 5 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
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); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
No subsequent dosing 

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renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
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. 
 
Dose Modifications for Overlapping Toxicities Pembrolizumab-Lenvatinib: 
 
Based on the known toxicity profiles of pembrolizumab and lenvatinib, certain treatment-related AEs 
are uniquely associated with one drug versus the other. For example, hypertension, arterial thrombotic 
events, proteinuria, and hemorrhagic events are known risks for lenvatinib treatment, while immune- 
related AEs are risks for pembrolizumab treatment. However, certain AEs, such as such as diarrhea, 
hypothyroidism, and liver enzyme elevation, may be initially considered attributable to either study 
drug. Therefore, evaluation of attribution is important for determining the study drug most likely related 
to the AE, or an alternative etiology, and subsequently proper clinical management. The following 
aspects should be considered: 
1. Timing of AE onset 
Since lenvatinib is dosed daily and continuously due to a relatively short half-life (28 hours), and 
pembrolizumab is dosed Q3W due to a long half-life, lenvatinib can be interrupted to assess 
whether an AE improves/resolves with dechallenge (ie, interruption of treatment) based on the 
following two scenarios: 
o If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab doses), only 
lenvatinib dose interruption is needed. 
o If an AE is identified at the beginning of a treatment cycle, lenvatinib can be interrupted 
and dosing of pembrolizumab should be held. 
If the subject recovers from an AE in response to lenvatinib interruption (ie, positive 
dechallenge), the event is more likely to be related to lenvatinib. Otherwise, after excluding other 
alternative explanations, an immune-related AE should be considered. 
 
2. Severity of AE 
If an AE is suspected to be treatment related and is severe/life threatening at the time of onset or 
is rapidly worsened, action including interrupting both drugs and initiating treatment with a 
corticosteroid (with exception of hypothyroidism, TIDM) and other supportive care should be 
taken promptly. 
 
3. Participants receiving the combination therapy (pembrolizumab + lenvatinib) must discontinue 
study therapy if any of the following occur: 
• ALT or AST >5 X ULN for more than 2 weeks. 
Pembrolizumab will have already been permanently discontinued per Table 6,[X], but 

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lenvatinib may be administered at a reduced dose by the time this criterion is met and must 
be permanently discontinued immediately. 
• ALT or AST >3 X ULN and (TBL >2 X ULN or INR >1.5). 
Although Table [X] advises pembrolizumab to be withheld (interrupted), and Table [X] 
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, both 
drugs must be permanently discontinued immediately. 
 
5.2.3 Monitoring Recommendations on lenvatinib 
 
• BP should be well-controlled prior to the start of lenvatinib. Blood pressure should be monitored 
after 1 week of treatment with lenvatinib, then every 2 weeks for the first 2 months and monthly 
thereafter while on treatment. If a patient develops systolic BP ≥140 mmHg or diastolic BP ≥90 
mmHg active management is indicated. 
 
• Urine protein should be monitored regularly. If urine dipstick ≥2+ is detected, dose interruptions, 
adjustments, or discontinuation may be necessary. Discontinue in the event of nephrotic syndrome. 
 
• Monitor and correct all electrolyte abnormalities in all patients. 
• Liver function tests should be monitored before initiation of treatment, then every 2 weeks for the 
first 2 months and monthly thereafter during treatment. In the case of hepatotoxicity, dose 
interruptions, adjustments, or discontinuation may be necessary. 
 
• Thyroid function, T4 and TSH should be monitored before initiation of, and periodically throughout 
treatment with lenvatinib. Hypothyroidism should be treated according to standard medical practice 
to maintain euthyroid state. 
 
• Monitor patients for clinical symptoms or signs of cardiac dysfunction as dose interruptions, 
adjustments, or discontinuation may be necessary. 
 
• Gastrointestinal toxicity should be actively managed in order to reduce the risk of development of 
renal impairment or renal failure. Dose interruptions, adjustments, or discontinuation may be 
necessary. 
 
• Withold lenvatinib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks 
following major surgery and until adequate wound healing. The safety of resumption of lenvatinib 
after resolution of wound healing complications has not been established. 
 
• Events of osteonecrosis of the jaw (ONJ) have been observed with lenvatinib. Invasive dental 
procedures are an identified risk factor for the development of ONJ. An oral dental examination and 
appropriate preventive dentistry should be considered prior to initiation of lenvatinib. Patients should 
be advised regarding periodic dental examinations and oral hygiene practice during lenvatinib 
therapy. Avoid invasive dental procedures during lenvatinib treatment, if possible. Use caution in 
patients receiving agents associated with ONJ, such as bisphosphonates and denosumab. 

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• Lenvatinib Dose Reductions/ Interruptions/ Discontinuation: 
• Dose reductions of Lenvatinib for treatment related toxicities will proceed as follows: 
o First dose reduction: 14 mg daily 
o Second dose reduction: 10 mg daily 
o Third dose reduction: 8 mg daily 
• Discontinuation: lenvatinib should be discontinued in case of life-threatening reactions (e.g., 
Grade 4) with the exception of laboratory abnormality judged to be nonlife-threatening, in 
which case they should be managed as severe reactions (e.g., Grade 3). 
• Dose interruption: Lenvatinib 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 2 weeks of treatment hold, 
unless otherwise discussed with the Sponsor Investigator. The reason for study intervention 
interruption is to be documented in the patient’s study record. 
 
5.2.4 Labeling, Packaging, Storage and Return Of Clinical Supplies 
 
5.2.4.1 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 products 
in accordance with the protocol and any applicable laws and regulations. 
 
Pembrolizumab and Lenvatinib will be provided by Merck as summarized in Table 8. 
 
Table 8 Product Descriptions 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
Lenvatinib 10 and 4 mg capsules 
Oral 
 
5.2.4.2 Packaging and Labeling Information 
 
Supplies will be labeled in accordance with regulatory requirements. 
 
5.2.4.3 Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
 
5.2.4.4 Storage and Handling Requirements 

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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. 
5.2.4.5 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck 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. 
 
5.3 Concomitant Medications/Vaccinations (allowed & prohibited) 
 
The investigator or qualified designee will record medication, if any, taken by the participant during the 
study. Concomitant medications will be recorded for 30 days after the last dose of study intervention. 
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, the Sponsor, and the participant. 
 
5.3.1 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 30 days after the last dose of trial intervention should be recorded. If participants experience an SAE 
or ECI, concomitant medications administered30 days after the last dose of trial intervention are to be 
recorded as defined in Section 6.2. 
 
5.3.2 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: 

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• Antineoplastic systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy 
• 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 and mRNA vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not 
allowed. 
 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from 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. There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.3.3 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 
4]. Where appropriate, these guidelines include the use of oral or IV treatment with corticosteroids, as 
well as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional supportive care. 
The treatment guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab. 
 
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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5.4 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 5.5). 
 
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 if 
agreed upon with the Sponsor 
 
• 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 and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment. 
• The participant has a confirmed positive serum pregnancy test 
Completion of pembrolizumab Q3W monotherapy consists of 35 treatments (approximately 2 years). 
Discontinuation of treatment may be considered for participants who have attained a confirmed 
complete response (CR) and have been treated for at least 8 cycles (at least 24 weeks), receiving [for 
monotherapy: at least 2 doses of pembrolizumab; for combination treatment: 2 cycles of the 
combination including 2 doses of pembrolizumab and at least 80% of the planned doses of 
lenvatinib beyond the date when the initial CR was declared. 

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5.5 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. 
 
Specified details regarding procedures to be performed at the time of withdrawal from the study are 
outlined in Section 6.1.6.1. 
 
5.6 
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 Merck decision to no longer supply study drug, adequate notification will be provided so 
that appropriate adjustments to participant treatment can be made. 
 
 
6.0 TRIAL ASSESSMENTS AND PROCEDURES 
 
6.1 Trial Procedures 
 
• Study procedures and their timing are summarized in the Schedule of Activities (SoA), Section 
2.3. 
 
• Adherence to the study design requirements, including those specified in the SoA, 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 

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• Additional evaluations/testing may be deemed necessary by the investigator, the Sponsor and/or 
Merck 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 or medically qualified 
designee must ensure appropriate documented informed consent is in place. 
 
6.1.1.2 General Informed Consent 
 
Informed 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 (or their legally 
acceptable representative) 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 
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. 

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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
 
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 until the first dose 
of study treatment (C1D1) 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. 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 
treatments, radiation and surgeries. 

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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 30 days after the 
last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the first dose of the 
new therapy. Once new anti-cancer therapy has been initiated the participant will move into survival 
follow-up. 
 
6.1.1.7 
Assignment of Screening Number 
 
All consented participants will be given a unique screening number that will be used to identify the 
participant for all procedures that occur. Each participant will be assigned only one screening number. 
Screening numbers must not be re-used for different participants. 
 
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 (see Appendix 5). 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 standard [specify if there are specific 
assessments that must be conducted as a minimum]. 
 
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. 

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Investigators should pay special attention to clinical signs related to previous serious illnesses. 
 
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 temperature, pulse, respiratory rate, weight and blood 
pressure. 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 and ECHO or MUGA 
 
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. 
A MUGA scan (using technetium-based tracer) or an echocardiogram will be performed to assess 
LVEF as designated in the SoA. MUGA or echocardiogram scans should be performed locally in 
accordance with the institution’s standard practice. MUGA scans are the preferred modality; 
however, whichever modality is used for an individual participant at baseline should be repeated for 
all subsequent LVEF assessments for that participant. LVEFs as assessed by the institution will be 
entered onto the CRF. Investigator assessment will be based upon institutional reports. 
 
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 

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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 
institution’s local laboratory require a change in study participant management or are considered 
clinically significant by the investigator (e.g., SAE or AE or dose modification), then the results 
must be recorded in the appropriate CRF (e.g., SLAB). 
 
• For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 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. 
 
Details regarding specific laboratory procedures/assessments to be performed in this study are provided 
below. The total amount of blood/tissue to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood/tissue volumes drawn/collected by visit and 
by sample type per participant can be found in the Lab Manual. Refer to the SoA (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 
 
All women who are being considered for participation in the study, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours or the first dose of 
study intervention. 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. 
 
6.1.4 Tumor Imaging and Assessment of Disease 
 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT). For the abdomen 
and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used when CT with 
iodinated contrast is contraindicated, or when local practice mandates it. 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 

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reproducibility of the assessment of existing and new tumor burden and improve the accuracy of the 
assessment of response or progression based on imaging. 
 
Brain imaging is required for all participants at screening. MRI is preferred; however, CT 
imaging will be acceptable, if MRI is medically contraindicated. Participant eligibility will be 
determined using local assessment (Investigator assessment) based on RECIST 1.1. In addition, 
images (including via other modalities) that are obtained at an unscheduled time point to 
determine disease progression, as well as imaging obtained for other reasons, but which 
demonstrate radiologic progression, should also be used to determine progression. 
 
When the Investigator identifies radiographic progression per RECIST 1.1, efforts should be 
made to verify radiologic PD. Treatment should continue until PD has been verified. Regardless 
of whether PD is verified, if the Investigator considers the participant has progressed, but elects 
to implement iRECIST, the Investigator will assess for confirmation of progression by iRECIST 
at subsequent time points. 
 
6.1.4.1 
Initial Tumor Imaging 
 
Initial tumor imaging at Screening must be performed within 30 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 30 days prior to 
C1D1. 
 
Brain imaging is required to rule out radiographically detectable brain metastases. Magnetic 
resonance imaging is preferred; however, CT imaging will be acceptable, if MRI is medically 
contraindicated or CT is mandated by local practice. 
 
6.1.4.2 
Tumor Imaging During the Study 
 
The first on-study imaging assessment should be performed at 9 weeks (±7 days) from the date 
of allocation. Subsequent tumor imaging should be performed every 9 weeks (±7 days) or more 
frequently if clinically indicated. After 1 year (±7 days), participants who remain on treatment 
will have imaging performed every 12 weeks (±7 days). 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. 
 
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a response is 
observed. Participants will then return to regular scheduled imaging every 9 weeks, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point. 

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Per iRECIST (Section 6.1.4.6), disease progression should be confirmed by the site 4 to 8 weeks 
after first radiologic evidence of PD in clinically stable participants. Participants who have 
unconfirmed disease progression may continue on treatment at the discretion of the investigator 
until progression is confirmed by the site provided they have met the conditions detailed in 
Section 6.1.4.6. Participants who receive confirmatory imaging do not need to undergo the next 
scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at the 
subsequent scheduled imaging time point, if clinically stable. Participants who have confirmed 
disease progression by iRECIST, as assessed by the site, will discontinue study treatment. 
Exceptions are detailed in Section 6.1.4.5. 
 
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. In participants who discontinue study treatment due to documented disease 
progression and the investigator elects not to implement iRECIST, this is the final required tumor 
imaging. 
 
For participants who discontinue study treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule used while on treatment (every 9 weeks in Year 1 or every 12 weeks 
after Year 1) to monitor disease status until the start of a new anticancer treatment, disease 
progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs 
first. 
 
6.1.4.4 
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). Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in total and 
5 per organ, if clinically relevant to enable a broader sampling of tumor burden. The first half of 
the flowchart in [Figure 2] illustrates the imaging flow involving verification of PD for clinically 
stable participants. 
 
6.1.4.5 
iRECIST Assessment of Disease 
 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor response 
and progression and make treatment decisions. When clinically stable, participants should not be 
discontinued until progression is confirmed by the investigator, working with local radiology, 
according to the rules outlined in Appendix 4. This allowance to continue treatment despite initial 
radiologic disease progression takes into account the observation that some participants can have 

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a transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response. This data will be captured in the clinical database. 
 
Clinical stability is defined as the following: 
 
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status 
• No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care 
 
Any participant deemed clinically unstable should be discontinued from study intervention at 
central verification of site-assessed first radiologic evidence of disease progression, and is not 
required to have repeat tumor imaging for confirmation of disease progression by iRECIST. 
 
If the investigator decides to continue treatment, the participant may continue to receive study 
intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm disease 
progression by iRECIST, per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective BICR. 
 
If repeat imaging does not confirm disease progression per iRECIST, as assessed by the 
investigator, and the participant continues to be clinically stable, study intervention may continue 
and follow the regular imaging schedule. If disease progression is confirmed, participants will be 
discontinued from study intervention. 
 
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 4, study 
intervention should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study intervention may be considered following 
consultation with the Sponsor. In this case, if study intervention is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 6 and submitted to 
the iCRO. 
 
A description of the adaptations and iRECIST process is provided in Appendix 4. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided in 
Table 6 and illustrated as a flowchart in Figures 1 and 2. 
 
Table 6 Imaging and Treatment After First Radiologic Evidence of Progressive Disease 

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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
Repeat imaging 
May continue study 
Repeat imaging at 4 
Discontinue treatment 
evidence of disease 
at 4 to 8 weeks to 
treatment at the 
to 8 weeks to 
progression by 
confirm disease 
assessment of the 
confirm disease 
RECIST 1.1 per 
progression 
investigator and 
progression per 
investigator assessment 
after the 
investigator’s 
participant’s consent 
discretion only. 
First radiologic 
Repeat imaging 
May continue study 
Repeat imaging at 4 
Discontinue treatment 
evidence of disease 
at 4 to 8 weeks to 
intervention at the 
to 8 weeks to 
progression by 
confirm disease 
investigator’s 
confirm disease 
RECIST 1.1 [For those 
progression. 
discretion while 
progression per 
studies in which PFS is 
Awaiting 
investigator’s 
the primary endpoint, 
confirmatory tumor 
discretion only. 
add the following: 
imaging by site by 
which has been verified 
iRECIST. 
by the central imaging 
vendor]. 
Repeat tumor imaging 
No additional 
Discontinue 
No additional 
Not applicable 
confirms disease 
imaging required. 
treatment (exception 
imaging required. 
progression (iCPD) by 
is possible upon 
iRECIST per 
consultation with 
investigator 
Sponsor). 
assessment. 
Repeat tumor imaging 
Repeat imaging 
Continue study 
Repeat imaging at 4 
Discontinue treatment 
shows iUPD by 
at 4 to 8 weeks to 
intervention at the 
to 8 weeks to 
iRECIST per 
confirm disease 
investigator’s 
confirm disease 
investigator 
progression. May 
discretion. 
progression per 
assessment. 
occur at next 
investigator’s 
regularly 
discretion only. 
scheduled 
imaging visit. 
Repeat tumor imaging 
Continue 
Continue study 
Continue regularly 
May restart study 
shows iSD, iPR, or iCR 
regularly 
intervention at the 
scheduled imaging 
intervention if 
by iRECIST per 
scheduled 
investigator’s 
assessments. 
condition has improved 
investigator 
imaging 
discretion. 
and/or clinically stable 
assessment. 
assessments. 
per investigator’s 
discretion. Next tumor 
imaging should occur 
according to the regular 
imaging schedule. 
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable disease; 
iUPD=iRECIST unconfirmed progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1; 
VOP=verification of progression 
[For studies in which PFS is the primary endpoint, add the following: Note: If progression has been centrally verified, 
further management is by the site, based on iRECIST. Any further imaging should still be submitted to the iCRO, but 
no rapid review will occur. If RECIST 1.1 disease progression has not been centrally verified, the site should continue 
treatment. Whether or not treatment continues, imaging should be collected and submitted to the iCRO with VOP 
request until RECIST 1.1 progression is verified by BICR.] 

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Figure 1: Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator 
 
 
 
 
 
6.1.5 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 
Tumor tissue and blood specimens will be collected and banked for correlative research studies. An 
additional optional collection for specimen banking will be collected for those who consent for at least 15 
subjects (in no certain order). Fresh tumor biopsy samples will be collected prior to initiating treatment. 
Archival tissue may be used in place of pre-treatment biopsy. A second biopsy will be collected on cycle 
3 day 8 (+/- 1 day). Blood specimens including the optional specimen banking samples will be collected 
during screening and on day 1 of cycles 1-6. 
 
Correlative and optional specimen banking samples collected for Screening may be used for C1D1 if the 
collection is within 3 days prior to C1D1. 
 
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 

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encouraged to continue to be followed for all remaining study visits as outlined in the SoA and Section 
6.2. 
 
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. 
 
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 
 
Please reference schedule of activities in section 2.3. 
 
6.1.7.2 
Treatment Period 
 
Please reference schedule of activities in section 2.3 
 
6.1.7.3 
Post-Treatment Visits 
 
6.1.7.3.1 
Safety Follow-Up Visit 
 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 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 
Efficacy 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 Efficacy Follow-Up 
Phase and should be assessed every 6 weeks (42 ± 7 days) by radiologic imaging to monitor disease 
status. After 1 year, the imaging time point will occur every 9 weeks (± 7 days). 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 as detailed in Section 5.2.3. 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. 

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The first survival follow-up assessment should be scheduled as described below: 
 
• For participants who discontinue treatment intervention and who will not enter the Efficacy 
Follow-up Phase, the first survival follow-up contact will be scheduled 12 weeks after the 
discontinuation visit and/or safety follow-up visit (whichever is last). 
 
For participants who completed assessments in the Efficacy Follow-up Phase, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up visit has 
been performed. 
 
6.1.7.3.4 
Post Study 
 
Participants will be required to return to clinic approximately 14 days after the last dose of study 
intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after the last 
dose of study intervention, a subsequent follow-up telephone call should be made at 14 days post 
the last dose of study intervention to determine of any AEs have occurred since the poststudy clinic 
visit. 
 
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 5. 
 
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 must be reported starting after the first dose of study 
intervention on C1D1. AEs, SAEs, and other reportable safety events that occur after the consent form is 
signed but before first dose of study intervention must be reported by the investigator only if the 
participant is receiving other run-in treatment, if the event causes 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 first dose of study intervention through 30 days following cessation of 
study intervention or until initiation of new anticancer therapy, whichever is earlier, must 
be reported by the investigator. 

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• All AEs meeting serious criteria, from the first dose of study intervention through 90 days 
following cessation of study intervention or 30 days following cessation of study intervention if 
the participant initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator. 
• 
Of note, progression of disease under study does not meet the definition of an Adverse 
Event, therefore death due to progression of disease under study is not reportable as 
an SAE. 
• All pregnancies and exposure during breastfeeding, from the first dose of study intervention 
through 120 days following cessation of study intervention, or 30 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 Merck 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 Merck. 
 
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and reported to 
Merck within the time frames as indicated in Table 7 via fax (Attn: Worldwide Product Safety; Fax 215-
661-6229). 
 
Table 7 Reporting Time Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events 
 
Type of Event 
Reporting Time 
Period: 
Consent to First 
Dose of Study 
Intervention 
Reporting Time 
Period: 
First Dose of 
Study 
Intervention  
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 Merck: 
Serious Adverse Event 
(SAE) including New 
Cancer Diagnosis and 
Overdose 
Report if: 
- due to protocol- 
specified 
procedure/interve
ntion 
- causes exclusion 
- participant is 
receiving 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 

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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 
in Appendix 5. 
 
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 Merck. 
 
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. 

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6.2.6 Events of Clinical Interest (ECIs) 
 
Selected nonserious and SAEs are also known as ECIs and must be reported to Merck. 
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 Merck product, the adverse event(s) is reported as a serious adverse 
event, even if no other seriousness criteria are met. 
 
2. 
For the purpose of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for: 
 
• 
Lenvatinib: any dose above the protocol-prescribed dose if associated with an adverse 
event 
 
There is no specific antidote for an overdose of lenvatinib. Due to its high degree of plasma 
protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients 
receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies at 
the recommended dose for differentiated thyroid cancer, RCC, and HCC. 
 
3. 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
 
*Note: These criteria are based upon available regulatory guidance documents. The purpose of the criteria 
is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology. 
 
7.0 STATISTICAL ANALYSIS PLAN 
 
7.1 Statistical Analysis Plan Summary 
 
For this exploratory pilot study, sample size was calculated based on a hypothesis of anticipated clinical 
efficacy and compared with historical clinical trial data. As this is a single arm study, no formal statistical 
comparisons will be made. 

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7.2 Statistical Analysis Plan 
 
This represents a single-arm signal finding pilot study. As such, no formal statistical comparisons will be 
conducted. However, using historical data from prospective clinical trials and retrospective case series 
reported in the literature, therapy with PD-1 inhibitors results in objective response rates of approximately 
10% and median progression free survival of approximately 3.5 months (reviewed by Wessely A., et al. 
International Journal of Molecular Sciences 2020) [27]. 
 
In this 30 patient pilot study, using a one-sided test with a type I error of 0.05, the power for detecting a 
difference in the ORR compared with the historical average of 10% ORR with anti-PD-1 monotherapy 
varies with the hypothetical experimental ORR as follows: 
 
Hypothetical experimental 
ORR 
Historical average ORR 
Power 
20% 
10% 
0.55 
25% 
10% 
0.78 
30% 
10% 
0.91 
 
Interim futility analysis/stopping rules: After 15 evaluable subjects have been enrolled and treated 
(defined as having received scheduled treatment per protocol for at least 1 cycle and have completed 
restaging imaging) - an interim futility analysis will be conducted. If the objective response rate is less 
than 20% (3 of 15 subjects) or the median progression free survival is less than 6 months - enrollment will 
stop. 
 
 
8.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
8.1 Data Reporting 
 
RedCap will be the electronic data capture (EDC) system utilized for data collection. Clinical data will 
be entered on electronic, study-specific case report forms (eCRFs) built and maintained in the eResearch 
application. All data entries to CRFs must be supported by a clinical source document. No direct entry 
of patient data to the CRF is permitted. 

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8.2 Continuing Review and Final Reports 
 
An annual progress report (continuing review) will be submitted to the FDA annually for the duration of 
the study and to the IRB of record at the interval it determines, but at least annually. Continuing review 
reports to the FDA will comply with Title 21, Part 312.33 of the Code of Federal Regulations. 
 
8.3 Protocol Modifications and Amendments 
 
All modifications or amendments to the protocol or informed consent document must be approved by 
the Principal Investigator and submitted to the IRB for review and approval. All modifications and 
amendments will be documented with a new version number and date. All changes to the informed 
consent document will include the date of the revision on the form. 
No changes will be implemented until IRB approval is obtained except when a potential threat to patient 
safety exists. 
The IRB will be notified of any significant deviations from the approved protocol. Documentation of all 
IRB correspondence will be maintained in a central regulatory file. 
 
8.4 Record Retention 
 
According to 21 CFR 312.62(c), the investigator shall retain required records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated. If no application is to be filed or if the application is not approved for such 
indication, the investigator shall retain these records until 2 years after the investigation is discontinued 
(IND is withdrawn) and the FDA is notified. 
The investigator must retain protocols, amendments, IRB/IBC approvals, copies of the Form FDA 1572, 
completed, signed, dated consent forms, patient source documents, case report forms, quality monitoring 
reports, drug accountability records and all documents of any nature regarding the study or patients 
enrolled. All records will be maintained under restricted access by the Clinical Trials Department at 
Providence Portland Medical Center while the study remains active. Records may be placed in long- 
term storage after the study is completed. The location of long-term storage will be secure and easily 
accessed for regulatory purposes. 
 
8.5 Study Monitoring 
 
Clinical research staff members who have completed specialized training in study monitoring 
procedures and human subjects’ protections perform study monitoring activities (Quality Control 
Reviews). Individuals who perform study monitoring activities do not report to Principal Investigators 
or research scientists and may not monitor studies for which they have direct responsibility. 
Study monitoring activities are conducted regularly and include (but are not limited to) review and 
verification of the following: 

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• Eligibility 
• Informed Consent process 
• Adherence to protocol treatment plan 
• Case Report Forms (CRFs) 
• Source Documentation 
• Adverse Events 
• Regulatory Reporting 
 
Results of study monitoring activities will be reported to applicable study personnel, the Administrative 
Director of Clinical Research and Quality Assurance. Quality Assurance (QA) personnel review study 
monitoring reports and, if necessary, determine follow-up actions to resolve significant findings. QA 
has the authority to request immediate corrective action if significant patient safety issues are identified. 
QA will track and trend results from study monitoring reports as well as associated corrective and 
preventive actions. A QA summary report will be provided to the IRB at the time of continuing review. 
QA personnel do not have a direct reporting relationship to the Principal Investigator and are not 
responsible for enrollment or coordination of care for study participants. 
External sites 
Monitoring will occur at intervals stipulated in the monitoring plan for the study. Monitoring may be 
performed on-site or remotely. Monitoring will include: review regulatory documentation, CRFs, 
source documentation, and investigational product storage, preparation, and accountability. The CRFs 
will be reviewed for completeness and accuracy compared to the source documents. 
 
8.6 Quality Assurance Plan 
 
The Providence Health System Quality Assurance (QA) plan for cancer clinical trials comprises 
Standard Operating Procedures (SOPs) that require ongoing review of activities associated with all 
investigator-initiated trials including protocol compliance, accuracy of data and safety of participants. 
Quality Assurance (QA) personnel review study monitoring reports and if necessary, determine follow- 
up actions to resolve significant findings. QA has the authority to request immediate corrective action if 
significant patient safety issues are identified. 
QA will track and trend results from study monitoring reports as well as associated corrective and 
preventive actions. A QA summary report will be provided to the IRB at the time of continuing review. 
QA personnel do not have a direct reporting relationship to the Principal Investigator and are not 
responsible for enrollment or coordination of care for study participants. 

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All case report forms will undergo quality assurance review. All quality assurance reviews will include 
verification of the accuracy and integrity of data entered to case report forms. Incorrect data will be 
identified and corrected. The existence of adequate source documents for all data will be verified. A 
staff person not associated with patient care coordination, data completion or submission will review all 
annual reports. 
 
 
8.7 Safety Monitoring Plan 
 
Oversight of participant safety will include review of adverse events as well as study progress and 
outcomes. 
Adverse events, outcomes, and recruitment and retention of patients will be reviewed on a weekly basis 
by the PI, research nurse, and data coordinator. Protocol deviations are reviewed monthly at the Cancer 
Research Meeting. 
 
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signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37- 
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plus pembrolizumab in patients with advanced endometrial cancer: an interim 
analysis of a multicentre, open-label, single-arm, phase 2 trial. The Lancet 
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plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. April 
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Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial 
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Mier, Allen L. Cohn, Margarita Romeo, Raquel Bratos, Marcia S. Brose, 
Christopher DiSimone, Mark Messing, Daniel E. Stepan, Corina E. Dutcus, 
Jane Wu, Emmett V. Schmidt, Robert Orlowski, Pallavi Sachdev, Robert 
Shumaker, and Antonio Casado Herraez 
Journal of Clinical Oncology 2020 38:26, 2981-2992 
Lee CH, Shah AY, Rasco D, Rao A, Taylor MH, Di Simone C, Hsieh JJ, Pinto 
A, Shaffer DR, Girones Sarrio R, Cohn AL, Vogelzang NJ, Bilen MA, 
Gunnestad Ribe S, Goksel M, Tennøe ØK, Richards D, Sweis RF, Courtright J, 
Heinrich D, Jain S, Wu J, Schmidt EV, Perini RF, Kubiak P, Okpara CE, Smith 
AD, Motzer RJ. Lenvatinib plus pembrolizumab in patients with either 
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Taylor MH, Lee CH, Makker V, Rasco D, Dutcus CE, Wu J, Stepan DE, 
Shumaker RC, Motzer RJ. Phase IB/II Trial of Lenvatinib Plus Pembrolizumab 
in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and 
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C, Heppt MV. The Role of Immune Checkpoint Blockade in Uveal Melanoma. 
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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 
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 (including 
LFT)/SGPT 
Total Protein 
Glucose [Indicate if 
fasting, or 
nonfasting] 
Calcium 
Alkaline 
phosphatase 
Thyroid Funtion 
Tests (LDH, Free 
T4, TSH) 
INR or PT and 
aPTT 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, nitrite, leukocyte esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
• 
24-hour urine collection for quantitative assessment of proteinuria may also be required 
at screening to determine eligibility 
Pregnancy 
Testing 
• 
Highly sensitive serum hCG pregnancy test (as needed for WOCBP) 
Other Screening 
Tests 
• 
FSH (as needed in WOCBP only) 
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 as 
described in Table 10 when having penile-vaginal intercourse with a woman of childbearing potential 
who is not currently pregnant. 

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○ 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 (with a failure rate of <1% per year) method of contraception that has a low user dependency 
consistently and correctly as described in Table 10 during the protocol-defined time frame in Section 
5.1.3.2. 
Table 10 Highly Effective Contraceptive Methods That Have Low User Dependency 
 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant a, b 
● 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) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation. 
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 120 days after the last dose of study treatment. 
 
Pregnancy Testing 
 
WOCBP should only be included after a negative highly sensitive serum pregnancy test. 

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Following initiation of treatment, pregnancy testing will be performed whenever an expected menstrual 
cycle is missed or when pregnancy is otherwise suspected; at the time points specified in the Schedule of 
Activities (Section 2.3), and as required locally. 

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Appendix 4: Description of the iRECIST Process for Assessment of Disease Progression 
 
Assessment at Screening and Prior to RECIST 1.1 Progression 
 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
 
Assessment and Decision at RECIST 1.1 Progression 
 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide whether 
to continue a participant on study treatment until repeat imaging 4 to 8 weeks later is obtained (using 
iRECIST for participant management (see Table 6 and Figures 1 and 2). This decision by the Investigator 
should be based on the participant’s overall clinical condition. 
 
Clinical stability is defined as the following: 
 
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status 
• No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at site-assessed 
first radiologic evidence of PD and is not required to have repeat tumor imaging for confirmation of PD 
by iRECIST. 
 
If the Investigator decides to continue treatment, the participant may continue to receive study treatment 
and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by iRECIST, per 
Investigator assessment. 
 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including: 
 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and ≥ 5 mm 
from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD 
(confirmed progressive disease). For purposes of iRECIST assessment, the first visit showing progression 
according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors 
caused the progression. 

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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as usual. 
 
New lesions will be classified as measurable or non-measurable, using the same size thresholds and rules 
as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up to 5 lesions total (up 
to 2 per organ), may be selected as New Lesions – Target. The sum of diameters of these lesions will be 
calculated and kept distinct from the sum of diameters for target lesions at baseline. All other new lesions 
will be followed qualitatively as New Lesions – Non-target. 
 
Assessment at the Confirmatory Imaging 
 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an overall 
response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), 
or as showing disease stability or response (iSD/iPR/iCR). 
 
Confirmation of Progression 
 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following 
occurs: 
 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, compared 
to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared to a 
prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time point 
 Visible growth of new non-target lesions 
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold 
(by RECIST 1.1) 
 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which iUPD is 
seen. This may correspond to the next visit in the original visit schedule. The assessment of the 

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subsequent confirmation scan proceeds in an identical manner, with possible outcomes of iCPD, iUPD, 
and iSD/iPR/iCR. 
 
Resolution of iUPD 
 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR 
if all lesions resolve. 
 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”. This means that the next visit that shows radiographic progression, whenever it 
occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a response 
of iCPD can be assigned. 
 
Management Following the Confirmatory Imaging 
 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the participant 
continues to be clinically stable, study treatment may continue and follow the regular imaging schedule. 
If PD is confirmed, participants will be discontinued from study treatment. 
 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment may be 
considered. In this case, if study treatment is continued, tumor imaging should continue to be performed 
following the intervals as outlined in Section 6. 
 
Detection of Progression at Visits After Pseudo-progression Resolves 
 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated by any of the 
following events: 
 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) either for 
the first time, or after resolution of previous pseudo-progression. The nadir is always the 
smallest sum of diameters seen during the entire trial, either before or after an instance of 
pseudo-progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD. 

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o If non-target lesions had shown previous unequivocal progression, and this progression has not 
resolved, iUPD results from any significant further growth of non-target lesions, taken as a 
whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion sum of 
diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation 
process (see Assessment at the Confirmatory Imaging above) is repeated. Progression must be confirmed 
before iCPD can occur. 
 
The decision process is identical to the iUPD confirmation process for the initial PD, except in one respect. 
If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the burden of new lesions 
has increased from its smallest value (for new target lesions, their sum of diameters is ≥5 mm increased 
from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the 
new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
 
Additional details about iRECIST are provided in the iRECIST publication [28]. 

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Appendix 5: 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 Merck product) 
includes any pharmaceutical product, biological product, vaccine, diagnostic agent, or protocol 
specified procedure whether investigational or marketed (including active comparator product, or 
run-in intervention), manufactured by, licensed by, provided by, or distributed by Merck 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. 
• Progression of disease under study. 
 
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. For example, death or hospitalization due to progression of disease under study would not be 
considered an SAE. 
 
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 Merck 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 

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substantial disruption. 
 
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 Merck in the same time frame as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck 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 Merck. 
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 Merck. 
• 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 
documented as the AE/SAE. 

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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 Merck product cause the AE? 
 
2. 
The determination of the likelihood that Merck 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 Merck’s product 
and the AE; the greater the correlation with the components and their respective elements (in 
number and/or intensity), the more likely Merck product caused the AE: 
 
• Exposure: Is there evidence that the participant was actually exposed to Merck 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 
Merck product? Is the time of onset of the AE compatible with a drug-induced effect (applies 
to studies with investigational medicinal product)? 

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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 Merck 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 Merck product; (3) the study is a 
single-dose drug study; or (4) Merck product(s) is/are only used 1 time.) 
 
• Rechallenge: Was the participant re-exposed to Merck 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) Merck 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 MERCK PRODUCT, OR IF RE-EXPOSURE TO MERCK’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 Merck 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 Merck product relationship). 

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• Yes, there is a reasonable possibility of Merck product relationship: 
• There is evidence of exposure to the Merck product. The temporal sequence of the AE onset 
relative to the administration of Merck product is reasonable. The AE is more likely explained 
by Merck product than by another cause. 
 
• No, there is not a reasonable possibility of Merck product relationship: 
• Participant did not receive the Merck product OR temporal sequence of the AE onset relative 
to administration of the Merck product is not reasonable OR the AE is more likely explained 
by another cause than the Merck 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 Merck. 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 Merck. 
 
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 one 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. 

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• The investigator will submit any updated SAE data to Merck within 2 business days but no longer 
than 3 calendar days of receipt of the information. 
 
10.1.5 Reporting of AEs, SAEs, and Other Reportable Safety Events to the Merck 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number: +1-215-661-6229 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European 
Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. 
Investigators will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally, 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; 
FAX 215-661-6229) at the time of submission to FDA.